Sudden cardiac death continues to be a major clinical problem in this country. The identification and prevention of sudden cardiac death in patients at high risk has not been effected much by newer diagnostic techniques nor new types of therapy. The one possible exception to the prevention of sudden cardiac death may be the use of beta-adrenergic blocking agents but most of these agents have serious side effects in some patients. The proposed Program is directed toward an understanding of the mechanisms underlying sudden cardiac death in an animal model (dog), and particularly the role of the autonomic nervous system. The model encompasses an anterior wall myocardial infarction in chronic dogs that are subsequently subjected to exercise plus posterior wall ischemia. Using this model it has been found that dogs are either susceptible or resistant to sudden cardiac death. There are three Projects and three Cores in the Program. Each Project will examine the autonomic nervous system mechanisms of lethal arrhythmias in the two groups of dogs at different levels of biological organization. Project I is directed toward an understanding of the differences in autonomic nervous system reflexes in the two groups and modification by daily exercise. Daily exercise has been shown to result in susceptible animals becoming resistant to sudden cardiac death. Project II will examine the cellular electrophysiological differences in the two groups using standard techniques and the interaction of adrenergic and muscarinic agonists. In addition, myocardial mapping will be accomplished to determine the potential locus for arrhythmias in this animal model. Project III will determine the potential difference in adrenergic and muscarinic receptors in the hearts from the two groups of animals and also examine the role of coupling systems in the myocardial membrane. Core A will function as the Administrative and Computer Core for the Program. Core B will be responsible for preparation of all experimental animals. Core C will examine the myocardial ultrastructure and coronary anatomy of the two groups of animals. The two major strengths of the Program are (1) the use of a single animal model studied at different levels of complexity to examine mechanisms and (2) the collaboration of three laboratories recognized for their own expertise. This Program should lead to an uncovering of the autonomic nervous system mechanisms responsible for sudden cardiac death and through knowledge of the basic mechanisms an ability to recommend methods for detection and improved treatment.